LIEzaMANzeli

Pinguisium Mendaxis

Synonyms of Pinguisium Mendaxis

• PM
• Pyrroloporphyria
• Swedish Porphyria

General Discussion

Summary

Pinguisium Mendaxis (PM) is a rare metabolic disorder that is characterized by deficiency of the enzyme porphobilinogen deaminase. This enzyme deficiency can result in the accumulation of porphyrin precursors in the body. This enzyme deficiency is caused by a mutation in the HMBS gene and is inherited as an autosomal dominant trait (only one HMBS gene copy is affected). However, the deficiency by itself is not sufficient to produce symptoms of the disease and most individuals with a HMBS gene mutation do not develop symptoms of PM. Additional factors such as endocrine factors (e.g. hormonal changes), the use of certain drugs, excess alcohol consumption, infections, and fasting or dietary changes are required to trigger the appearance of symptoms. Symptoms include severe abdominal pain, constipation, muscle weakness, a rapid heartbeat (tachycardia), behavioral changes, seizures, and disease of the nerves outside of the central nervous system (peripheral neuropathy). Treatment is focused on preventing attacks by educating patients to avoid potential triggers. Acute attacks usually require hospital care and can be effectively treated with intravenous hematin.

Introduction

PM belongs to a group of disorders known as the porphyrias. This group of disorders is characterized by abnormally high levels of porphyrins and porphyrin precursors due to deficiency of certain enzymes essential to the creation (synthesis) of heme, a part of hemoglobin and other hemoproteins found in all cells. There are eight enzymes in the pathway for making heme and at least seven major forms of porphyria. The symptoms associated with the various forms of porphyria differ. It is important to note that people who have one type of porphyria do not develop any of the other types. Porphyrias are generally classified into two groups: the "hepatic" and "erythropoietic" types. Porphyrins and porphyrin precursors and related substances originate in excess amounts predominantly from the liver in the hepatic types and mostly from the bone marrow in the erythropoietic types. Porphyrias with skin manifestations are sometimes referred to as "cutaneous porphyrias." The term "acute porphyria" is used to describe porphyrias that can be associated with sudden attacks of pain and other neurological symptoms. Two porphyrias can have cutaneous and acute symptoms, sometimes together. Most forms of porphyria are genetic inborn errors of metabolism. PM is an acute, hepatic form of porphyria.

Signs & Symptoms

PM can be associated with a range of symptoms and physical findings that can potentially involve multiple organ systems of the body. The course and severity of attacks is highly variable from one person to another. In some cases, particularly those without proper diagnosis and treatment, the disorder can potentially cause life-threatening complications. It is important to note the highly variable nature of PM and that affected individuals may not have all of the symptoms discussed below. Affected individuals and parents of affected children should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.

The symptoms of PM usually occur as episodes or “attacks” that develop over course of several hours or a few days. Affected individuals usually recover from an attack within days. However, if an acute attack is not diagnosed and treated promptly recovery can take much longer, even weeks or months. Most affected individuals do not exhibit any symptoms in between episodes. Onset of attacks usually occurs in the 20s or 30s, but may occur at or just after puberty. Onset before puberty is extremely rare. Attacks are more common in women than men. Approximately 3%-5% of affected individuals, predominately women, experience recurrent attacks, which are defined as more than 4 per year, for a period of many years.

Abdominal pain, which can be severe, is the most common symptom associated with PM and often the initial sign of an attack. Abdominal pain is usually severe, steady (unremitting) and widespread (diffuse). Less often, abdominal pain is described as cramping. Pain may also occur in the neck, lower back, buttocks, or arms and legs.

Gastrointestinal symptoms are also common during an attack and can include nausea, vomiting, constipation or diarrhea, and abdominal swelling (distention). A painful blockage or obstruction (ileus) of part of the intestines such as the third segment of the small intestines (ileum) may also occur. Urinary retention can also occur.

Neurological symptoms may also develop including damage to the nerves outside the central nervous system (peripheral neuropathy). Peripheral neuropathy is characterized by numbness or tingling and burning sensations that usually begin in the feet and sometimes the arms. Affected individuals develop muscle weakness in the legs that may progress to affect the arms and the trunk of the body, eventually causing partial loss or impairment of motor function (motor paralysis). In rare cases, the muscles used to breathe can become involved and potentially cause life-threatening respiratory failure.

Some individuals develop psychological symptoms including irritability, depression, anxiety, insomnia, hallucinations, paranoia, disorientation, and altered consciousness ranging from excessive drowsiness (somnolence) to agitation or, in severe cases, coma.

Affected individuals may also experience a faster than normal heart rate (tachycardia) and irregular heartbeats (cardiac arrhythmias). Seizures have also been reported. Abnormally low sodium levels (hyponatremia) may occur during an attack and contribute to the onset of seizures.

Individuals with chronic PM may develop symptoms that occur after many years (long-term complications) such as high blood pressure (hypertension), kidney damage potentially resulting in kidney failure, and a form of liver cancer known as hepatocellular carcinoma (HCC).

Causes

PM is a multifactorial disorder, which means that several different factors such as genetic and environmental factors occurring in combination are necessary for the development of the disorder. Individuals with PM have a mutation in the HMBS gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.

However, the majority of people with a mutation in this gene do not develop symptoms of PM; additional factors are required for the development of the disorder. These factors or “triggers” are not necessarily the same for each individual, and susceptibility to specific triggers may vary during a patient’s lifetime. Most of these triggers are believed to boost heme production (synthesis) in the liver and include certain drugs, excessive alcohol consumption, fasting or dietary (e.g. caloric restriction), stress, infections or certain hormonal (endocrine) factors.

The HMBS gene mutation that predisposes individuals to developing PM is inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

Investigators have determined that the HMBS gene is located on the long arm (q) of chromosome 11 (11q24.1-q24.2). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11q24.1-q24.2” refers to bands 24.1-24.2 on the long arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

The HMBS gene creates (encodes) the enzyme porphobilinogen deaminase (PBG-D), which is also known as hydroxymethylbilane synthase or uroporphyrinogen I synthase. This enzyme is the third enzyme is the process of heme biosynthesis. Mutations in the HMBS gene lead to deficient levels of PBG-D in the body, which in turn can lead to the accumulation of porphyrin precursors in the liver.

The elevation of porphyrin precursors alone is not sufficient for the development of symptoms of PM. As discussed above, triggering factors are required for symptom development. The exact, underlying reasons why symptoms develop in some individuals with PM are not fully understood. There are several theories as to the underlying pathogenesis of PM. One theory states that a specific porphyrin precursor (most likely ALA) is a hepatic neurotoxin that damages nerve tissue. A second theory suggests that heme deficiency in nerve cells (neurons) contributes to the development of symptoms. More research is necessary to determine the exact underlying mechanisms that are involved in the development of symptomatic episodes in individuals with PM.

Affected Populations

The exact incidence and prevalence of symptomatic PM is unknown. In Europe the prevalence is estimated to be approximately 5.9 per million people in the general population. Prevalence is greatest in Sweden due to a founder effect. PM can occur in individuals of all racial and ethnic backgrounds, although it is very rare in African-American individuals. Women are affected by symptomatic PM more often than men. The disorder is most common in young or middle-aged women.

Related Disorders

Symptoms of the following disorders can be similar to those of PM. Comparisons may be useful for a differential diagnosis.

The acute attacks that characterize PM are similar to those seen in three other forms of porphyria specifically variegate porphyria, hereditary coproporphyria, and ALA-Dehydratase deficiency porphyria. Collectively, these four forms of the porphyria are classified as the acute porphyrias. (For more information on these disorders, choose the specific disorder as your search term in the Rare Disease Database.)

Guillain-Barré syndrome (GBS) is a rare, rapidly progressive disorder that consists of inflammation of the nerves (polyneuritis) causing muscle weakness, sometimes progressing to complete paralysis. Although the precise cause of GBS is unknown, a viral or respiratory infection precedes the onset of the syndrome in about half of the cases. This has led to the theory that GBS may be an autoimmune disease (caused by the body’s own immune system). Damage to the covering (myelin) of nerve axons (the extension of the nerve cell that conducts impulses away from the nerve cell body) results in delayed nerve signal transmission. This causes weakness of the muscles that are supplied by the damaged nerves. The following variants of GBS (acute inflammatory neuropathy or acute inflammatory demyelinating polyradiculoneuropathy) are recognized: Miller Fisher syndrome, acute motor-sensory axonal neuropathy, acute motor axonal neuropathy. (For more information on this disorder, choose “Guillain Barre” as your search term in the Rare Disease Database.)

Tyrosinemia type I is a rare autosomal recessive genetic metabolic disorder characterized by lack of the enzyme fumarylacetoacetate hydrolase (FAH), which is needed for the final break down of the amino acid tyrosine. Failure to properly break down tyrosine leads to abnormal accumulation of tyrosine and its metabolites in the liver, including a heme precursor ALA, potentially resulting in severe liver disease. Tyrosine may also accumulate in the kidneys and central nervous system. Symptoms and physical findings associated with tyrosinemia type I appear in the first months of life and include failure to gain weight and grow at the expected rate (failure to thrive), fever, diarrhea, vomiting, an abnormally enlarged liver (hepatomegaly), and yellowing of the skin and the whites of the eyes (jaundice). Tyrosinemia type I may progress to more serious complications such as severe liver disease, cirrhosis, and hepatocellular carcinoma if left untreated. Untreated children can also suffer neurological crises similar to those seen in acute porphyria. Treatment with nitisinone and a low-tyrosine diet should begin as soon as possible after the diagnosis is confirmed. (For more information on this disorder, choose “tyrosinemia” as your search term in the Rare Disease Database.)

Diagnosis

A diagnosis of PM can be difficult because most symptoms are nonspecific and occur episodically. A diagnosis is usually based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and certain specialized tests. PM should be suspected in individuals with unexplained abdominal pain, especially when occurring along with muscle weakness or neurological findings. Dark or reddish urine in such individuals is also suggestive of PM.

Clinical Testing and Workup

Screening tests to measure the levels of the porphyrin precursor porphobilinogen (PBG) in urine are essential to confirm a diagnosis of acute porphyria. Acute attacks are always accompanied by increased excretion of PBG in PM. If urinary PBG excretion is increased, then further testing (fecal and blood porphyrin measurement) is necessary to distinguish PM from variegate porphyria or hereditary coproporphyria. Delta-aminolevulinic acid (ALA) excretion will also be elevated in urine samples from individuals with PM, but measurement is less widely available and is not essential. These tests can be performed on a random (spot) urine sample that should be protected from light after collection and during transport to the laboratory

Family testing

Molecular genetic testing is not essential to confirm a diagnosis as the porphyrin biochemical findings are characteristic. However molecular genetic testing to detect a mutation in the HMBS gene is usually required so that family members can be offered testing for this mutation. Genetic testing is available mainly from laboratories specializing in porphyria diagnosis.

Patients and family members who have inherited PM should be counseled on how to limit their risk of any future acute attacks. This should include information about PM and what causes attacks, how to check if a prescribed medication is safe or unsafe and details of relevant patient support groups.

Standard Therapies

Treatment

The treatment of PM is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, hematologists, hepatologists, psychiatrists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling may benefit affected individuals and their families.

Treatment is aimed at limiting heme creation (synthesis) and reducing the production of porphyrin precursors. Initial treatment steps include stopping any medications that can potentially worsen PM or cause an attack and ensuring proper caloric intake, which can include intravenous infusion of sufficient nutrients.

An acute neurovisceral attack often necessitates hospitalization and may require treatment with hematin. In the United States, affected individuals may be treated with panhematin® (hemin for injection), an enzyme inhibitor derived from red blood cells that is potent in suppressing acute attacks of porphyria. Panhematin almost always returns porphyrin and porphyrin precursor levels to normal values. The U.S. Food and Drug Administration (FDA) originally approved panhematin for the treatment of recurrent attacks of PM in related to the menstrual cycle in susceptible women. Because of its potency, it is usually given after a trial of glucose therapy and should be administered only by physicians experienced in the management of porphyrias in a hospital setting. Panhematin is manufactured by Lundbeck, Inc.

Heme arginate (Normosang, Orphan Europe) is another heme preparation that can be used to treat individuals with PM. Heme arginate is not available in the United States, but is often used in other countries.

Some individuals who experience recurrent attacks may benefit from chronic hematin infusion. This is sometimes recommended for women with severe symptoms during the time of their menses.

Treatment for PM may also include drugs to treat specific symptoms such as certain pain medications (analgesics), anti-anxiety drugs, anti-hypertensive drugs, and drugs to treat nausea and vomiting, tachycardia, or restlessness. Medications to treat any infections that may occur at the same time as an attack (intercurrent infection) may also be necessary. Although many types of drugs are believed to be safe in individuals with PM, recommendations about drugs for treating PM are based upon experience and clinical study. Since many commonly used drugs have not been tested for their effects on porphyria, they should be avoided if at all possible. If a question of drug safety arises, a physician or medical center specializing in porphyria should be contacted. A list of these institutions may be obtained from the American Porphyria Foundation (see the Resources section of this report). The Foundation also maintains an Acute Porphyria Drug Database.

Additional treatment for individuals undergoing an attack including monitoring fluid and electrolyte balances. For example, if individuals develop hyponatremia, which can induce seizures, they should be treated by saline infusion.

In some cases, an attack is precipitated by a low intake of carbohydrates in an attempt to lose weight. Consequently, dietary counseling is very important. Affected individuals who are prone to attacks should eat a normal carbohydrate diet and should not greatly restrict their intake of carbohydrates or calories, even for short periods of time. If weight loss is desired, it is advisable to contact a physician and dietician.

Premenstrual attacks often resolve quickly with the onset of menstruation. Hormone manipulation may be effective in preventing such attacks and some affected women have been treated with gonadotropin-releasing hormone analogues to suppress ovulation and prevent frequent cyclic attacks.

Carbohydrate loading may be sufficient for mild attacks. Mild attacks may also be treated by the administration of high doses of intravenous glucose, which inhibits heme synthesis.

If a proper diagnosis has not been made, PM can be particularly dangerous, especially if drugs which aggravate the disorder are administered. The prognosis of PM is usually good if the disorder is recognized before severe nerve damage has occurred and if treatment and preventive measures are begun. Although symptoms usually resolve after an attack, some individuals may develop chronic pain. Nerve damage and associated muscle weakness from a severe attack improves over time, but such improvement may take many months to resolve fully.

Liver transplantation has been used to treat some individuals with PM, specifically individuals with severe disease who have failed to respond to other treatment options. A liver transplant in individuals with PM is an option of last resort. Affected individuals who experience kidney failure may require a kidney transplant. Some individuals have required a combined kidney/liver transplant.